IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors

Molecular Cancer

Research

Dietrich von Schweinitz¹  Melanie Eichenmüller¹  Saskia Joppien¹  Roland Kappler¹  Beate Häberle¹  Ivonne Regel¹  Angelika Vollmar²  Johanna Liebl²  Josef Müller-Höcker³ 

[1] Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, 80337, Munich, Federal Republic of Germany;Department of Pharmaceutical Biology, Ludwig-Maximilians-University Munich, 81377, Munich, Federal Republic of Germany;Institute of Pathology, Ludwig-Maximilians-University Munich, 80337, Munich, Federal Republic of Germany;

关键词: Hepatoblastoma;    Epigenetics;    Methylation;    Invasion;    IGF2;   

DOI  :  10.1186/1476-4598-11-9

 received in 2011-09-01, accepted in 2012-03-08,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundHepatoblastoma (HB) is an embryonal liver neoplasm of early childhood with a poor prognosis for patients with distant metastases and vascular invasion. We and others have previously shown that the overexpression of insulin-like growth factor 2 (IGF2), loss of imprinting at the IGF2/H19 locus, and amplification of pleomorphic adenoma gene 1 (PLAG1) are common features in HB, suggesting a critical role of the IGF axis in hepatoblastomagenesis. In this study, we investigated the role of the insulin-like growth factor binding protein 3 (IGFBP3), a known competitor of the IGF axis, in pediatric liver cancers.ResultsThe IGFBP3 gene was highly expressed in normal pediatric livers but was heavily downregulated in four HB cell lines and the majority of HB primary tumors (26/36). Detailed methylation analysis of CpG sites in the IGFBP3 promoter region by bisulfite sequencing revealed a high degree of DNA methylation, which is causatively associated with the suppression of IGFBP3 in HB cell lines. Consequently, the treatment of HB cell lines with 5-aza-2'-deoxycytidine resulted in DNA demethylation and reactivation of the epigenetically silenced IGFBP3 expression. Interestingly, IGFBP3 promoter methylation predominantly occurred in metastatic HB with vascular invasion. Restoring IGFBP3 expression in HB cells resulted in reduced colony formation, migration, and invasion.ConclusionThis study provides the first direct evidence that the reactivation of IGFBP3 decreases aggressive properties of pediatric liver cancer cells and that IGFBP3 promoter methylation might be used as an indicator for vessel-invasive tumor growth in HB patients.

【 授权许可】

Unknown   
© Regel et al; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.